Project Summary/Abstract Oral mucosa is prone to disorders such as trauma, congenital defects, and acquired diseases (e.g., cancer). Meanwhile, oral mucosa serves as a barrier to protect the underlying tissues, which is achieved through the continual replacement of cells originating from a presumable reservoir of stem cells in the basal layer. Currently, the identity of stem cells in oral mucosa is largely unknown, preventing further mechanistic studies to fully un- derstand their self-renewal, differentiation and regeneration capacity. I have developed a repertoire of transgenic lineage tracing mice and identified a Wnt-responsive population that functions as a stem cell pool in the oral epithelia. In this proposed project, I will thoroughly characterize the contribution(s) of these Wnt-responsive stem cells in oral mucosa during homeostasis (Aim1), injury repair (Aim2), and malignancy (Aim3). My central hypoth- esis is that in oral mucosa, Wnt-responsive cells maintain the tissue integrity and effectuate the regeneration following injury, and mutation of this same population initiates oral cancer. These aims will utilize lineage tracing, lineage ablation, label retention, and injury and oral cancer models to interrogate stem cell maintenance, regen- erative dynamics as well as the cells of origin in cancer. These studies are designed to enrich our knowledge about the distribution of stem cells in oral mucosa and how those cells contribute to the integrity and healing ability of oral mucosa. This understudied area has great potential to revolutionize the therapeutic approaches for regeneration of tissues in the craniofacial complex, including skin and mucosa. Successful completion of this project will also advance our knowledge of cancer stem cells, providing novel targets for oral cancer treatment. Aim 2 and 3 will be initiated under the mentorship of Dr. Jill Helms (Stanford University), Dr. Daniel Ramos (UCSF) and Dr. Sinha Satrajit (University at Buffalo) and completed during the R00 period, whereas Aim 1 will be completed before the end of the K99 phase. This project has been designed to facilitate my career goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution. I plan to develop an independent research program relying on state-of-the-art genetic mouse models to address unsolved questions in oral mucosa with clear relevance to human health. Besides the dedicated research time, I will take coursework and attend seminars to update my knowledge in the rapidly evolving fields of stem cell biology and cancer biology at Stanford University which hosts one of the most experienced and thriving communities of cancer and stem cell biologists in the world. I will also learn advanced biostatistics to improve experiment design and data interpretation. To prepare for the transition into an independent investigator pursuing R01-level funding, I will be actively engaged in learning grant writing, teaching, mentoring and communication skills from my mentor and advisors, and also from the interactive lectures and coaching sessions offered from Stanford University.